世界生命科学前沿动态周报（五十）

【点评】
    该研究发现了除了雌激素与乳腺癌有关，雄性激素与乳腺癌也有关系。为治疗雌激素受体阴性的乳腺癌患者的研究开辟了道路。

【参考论文】Cancer Cell, 2011; 20 (1): 119-131 DOI: 10.1016/j.ccr.2011.05.026
Targeting Androgen Receptor in Estrogen Receptor-Negative Breast Cancer
Min Ni, Yiwen Chen, Elgene Lim, et al.
Endocrine therapies for breast cancer that target the estrogen receptor (ER) are ineffective in the 25% 30% of cases that are ER negative (ER ). Androgen receptor (AR) is expressed in 60% 70% of breast tumors, independent of ER status. How androgens and AR regulate breast cancer growth remains largely unknown. We find that AR is enriched in ER breast tumors that overexpress HER2. Through analysis of the AR cistrome and androgen-regulated gene expression in ER /HER2+ breast cancers we find that AR mediates ligand-dependent activation of Wnt and HER2 signaling pathways through direct transcriptional induction of WNT7B and HER3. Specific targeting of AR, Wnt or HER2 signaling impairs androgen-stimulated tumor cell growth suggesting potential therapeutic approaches for ER /HER2+ breast cancers.

3. 定量的表观遗传记忆背后的基于多梳的开关
【动态】
　　保守的多梳抑制复合物2（PRC2）进行的组蛋白3赖氨酸27三甲基化（H3K27me3）与稳定的表观遗传静默有关。对PRC2诱导的基因静默已有很多了解，但关键问题还是关于它的聚集和稳定性。植物对冬天的感知和记忆，即春化现象，在拟南芥是一个涉及基于PRC2的花抑制子FLC的静默的经典表观遗传过程。春化现象缓慢的动力学表现为在冷天需数周时间才能发生，在接下来的暖日子产生一定水平的定量取决于之前冷天长度的稳定的FLC静默。这些特点使春化现象成为理想的试验体系来研究表观遗传状态的维持和转换。英国科学家使用数学模型、染色质免疫沉淀和FLC:GUS报告分析，说明了在细胞数量取决于之前冷天数的一个细胞亚群中春化现象的数量化本性产生于H3K27me3介导的暖天FLC静默。在冷天期间，在FLC上紧靠聚集区域的地方H3K27me3水平日渐增加。在冷天结束时，数字模拟预测这样的一个聚集区域能够转换个别位置的双稳态的表观遗传状态，通过静默取决于冷天暴露时长的H3K27me3标记而可能涵盖整个FLC。因此，该模型预测了在单个细胞中FLC基因表达的一种双稳态模式，一种用FLC:GUS报告体系确认的预测。该研究提出的转换机制，涉及一个相反作用组蛋白修饰的局部聚集，很可能与广泛的表观遗传重组有关。

【点评】
　该研究解释了生物体如何对一些变化的环境条件形成生物学记忆，发现记忆机制是一类生物学开关并能遗传给后代的表观调控。

【参考论文】Nature, 2011; DOI:10.1038/nature10241
A Polycomb-based switch underlying quantitative epigenetic memory
Andrew Angel, Jie Song, Caroline Dean, Martin Howard.
The conserved Polycomb repressive complex 2 (PRC2) generates trimethylation of histone 3 lysine 27 (H3K27me3), a modification associated with stable epigenetic silencing. Much is known about PRC2-induced silencing but key questions remain concerning its nucleation and stability. Vernalization, the perception and memory of winter in plants, is a classic epigenetic process that, in Arabidopsis, involves PRC2-based silencing of the floral repressor FLC. The slow dynamics of vernalization, taking place over weeks in the cold, generate a level of stable silencing of FLC in the subsequent warm that depends quantitatively on the length of the prior cold. These features make vernalization an ideal experimental system to investigate both the maintenance of epigenetic states and the switching between t em. Here, using mathematical modelling, chromatin immunoprecipitation and an FLC:GUS reporter assay, we show that the quantitative nature of vernalization is generated by H3K27me3-mediated FLC silencing in the warm in a subpopulation of cells whose number depends on the length of the prior cold. During the cold, H3K27me3 levels progressively increase at a tightly localized nucleation region within FLC. At the end of the cold, numerical simulations predict that such a nucleation region is capable of switching the bistable epigenetic state of an individual locus, with the probability of overall FLC coverage by silencing H3K27me3 marks depending on the length of cold exposure. Thus, the model predicts a bistable pattern of FLC gene expression in individual cells, a prediction we verify using the FLC:GUS reporter system. Our proposed switching mechanism, involving the local nucleation of an opposing histone modification, is likely to be widely relevant in epigenetic reprogramming.

4. 遗传性乳腺癌遗传预期与端粒缩短相关
【动态】  
    越来越多的证据表明短的端粒和相应的基因不稳定性对细胞恶性转变负有责任。家族性乳腺癌已观察到有遗传性。西班牙的科学家假设引发此病的基因缺陷会影响端粒的维护导致端粒缩短，研究了家族性乳腺癌病人的端粒长度。他们首先研究了623个乳腺癌家族中母女对的发病年龄预期，分类为BRCA1, BRCA2, 和BRCAX。此外， 用定量PCR分析了198例遗传性乳腺癌病人外周血白血球中DNA端粒的长度，并与267例对照样本和71例偶发的乳腺癌病人样本进行了比较。同时也评估了乳腺癌家族母女对和对照样本的端粒长度变化来查看代间差异，发现短的端粒是遗传性而不是偶发性乳腺癌的特征。他们确定了一组带有短端粒的乳腺癌家族BRCAX，提示端粒维护基因可能是乳腺癌的敏感基因。值得注意的是，他们描述了端粒的渐进性缩短与受影响家族连续传代时乳腺癌的越来越早发生有联系，并为此提供了证据，提示这可能是遗传性乳腺癌遗传预期的机理。

【点评】
    该研究发现了端粒异常与遗传性乳腺癌之间的关联，即越来越短的端粒与越来越早发生遗传性乳腺癌之间有关联。

【参考论文】PLoS Genetics, 2011; 7 (7): e1002182 DOI:10.1371/journal.pgen.1002182
Genetic Anticipation Is Associated with Telomere Shortening in Hereditary Breast Cancer
Beatriz Martinez-Delgado, Kira Yanowsky, Lucia Inglada-Perez, et al.
There is increasing evidence suggesting that short telomeres and subsequent genomic instability contribute to malignant transformation. Telomere shortening has been described as a mechanism to explain genetic anticipation in dyskeratosis congenita and Li-Fraumeni syndrome. Since genetic anticipation has been observed in familial breast cancer, we aimed to study telomere length in familial breast cancer patients and hypothesized that genetic defects causing this disease would affect telomere maintenance resulting in shortened telomeres. Here, we first investigated age anticipation in mother-daughter pairs with breast cancer in 623 breast cancer families, classified as BRCA1, BRCA2, and BRCAX. Moreover, we analyzed telomere length in DNA from peripheral blood leukocytes by quantitative PCR in a set of 198 hereditary breast cancer patients, and compared them with 267 control samples and 71 sporadic breast cancer patients. Changes in telomere length in mother-daughter pairs from breast cancer families and controls were also evaluated to address differences through generations. We demonstrated that short telomeres characterize hereditary but not sporadic breast cancer. We have defined a group of BRCAX families with short telomeres, suggesting that telomere maintenance genes might be susceptibility genes for breast cancer. Significantly, we described that progressive telomere shortening is associated with earlier onset of breast cancer in successive generations of affected families. Our results provide evidence that telomere shortening is associated with earlier age of cancer onset in successive generations, suggesting that it might be a mechanism of genetic anticipation in hereditary breast cancer.

5. 人体诱导多能干细胞藏有致病性线粒体DNA突变
【动态】
    人体诱导多能干细胞最近被发现会藏有基因组修改，但重组细胞线粒体DNA的完整性还没有研究。线粒体DNA突变率很高，被认为对很多人体疾病负有责任。而且，线粒体DNA失去完整性可能会改变细胞的能量代谢，限制细胞分化。以前证明了诱导多能干细胞的产生与线粒体重构和向糖解代谢转换有关的一个德国研究组最近又测定了细胞重组对线粒体DNA的完整性的影响。针对线粒体DNA的大规模平行焦磷酸测序显示来源于年轻健康供体的人体诱导多能干细胞藏有单个碱基的线粒体DNA突变（替换、插入、删除），既有同质的（在所有线粒体DNA分子）又有异质的（在一部分线粒体DNA分子）。有趣的是，异质性水平在来源于同一父代纤维母细胞的诱导多能干细胞系间也各不相同，这一现象很可能可用于开发生产来源于线粒体疾病患者的无线粒体DNA突变的诱导多能干细胞。通过整合转录、代谢和有效的生物能量学几方面的数据，该研究揭示了带有不同程度线粒体DNA突变的诱导多能干细胞系维持了恒定的人体胚胎干细胞样的能量代谢重组。这包括过表达糖解酶，增加G6P的量，高表达PDK1蛋白，从而将生物能量流线路转向糖解。总之，尽管诱导多能干细胞中的线粒体DNA突变不影响重组相关的代谢调整，在分析诱导多能干细胞系时致病性线粒体DNA修饰的出现还是要监控的一个重要方面。

【点评】
    诱导多能干细胞中的线粒体DNA突变虽不影响重组细胞的代谢路线调整，但依然存在比较高的致病风险，大大限制了其实用性。